MiR-205-5p inhibition by locked nucleic acids impairs metastatic potential of breast cancer cells

Mir-205 plays an important role in epithelial biogenesis and in mammary gland development but its role in cancer still remains controversial depending on the specific cellular context and target genes. We have previously reported that miR-205-5p is upregulated in breast cancer stem cells targeting ERBB pathway and leading to targeted therapy resistance. Here we show that miR-205-5p regulates tumorigenic properties of breast cancer cells, as well as epithelial to mesenchymal transition. Silencing this miRNA in breast cancer results in reduced tumor growth and metastatic spreading in mouse models. Moreover, we show that miR-205-5p knock-down can be obtained with the use of specific locked nucleic acids oligonucleotides in vivo suggesting a future potential use of this approach in therapy

How to combine CTA, 99mTc-WBC SPECT/CT, and [18F]FDG PET/CT in patients with suspected abdominal vascular endograft infections?

Purpose - We aimed at comparing Tc-99m-HMPAO white blood cells (Tc-99m-WBC) scintigraphy, 18fluorine-fluorodeoxyglucose ([F-18]FDG) positron emission tomography/computed tomography (PET/CT) and CT angiography (CTA) in patients with suspected abdominal vascular graft or endograft infection (VGEI). Moreover, we attempted to define a new visual score for interpreting [F-18]FDG PET/CT scans aiming at increasing its specificity. Methods - We prospectively compared Tc-99m-WBC SPECT/CT, [F-18]FDG PET/CT, and CTA in 26 patients with suspected abdominal VGEI. WBC scans were performed and interpreted according to EANM recommendations. [F-18]FDG PET/CT studies were assessed with both qualitative (Sah's scale and new visual score) and semi-quantitative analyses. CTA images were interpreted according to MAGIC criteria. Microbiology, histopathology or a clinical follow-up of at least 24 months were used to achieve final diagnosis. Results - Eleven out of 26 patients were infected. [F-18]FDG PET/CT showed 100% sensitivity and NPV, with both scoring systems, thus representing an efficient tool to rule out the infection. The use of a more detailed scoring system provided statistically higher specificity compared to the previous Sah's scale (p = 0.049). Tc-99m-WBC SPECT/CT provided statistically higher specificity and PPV than [F-18]FDG PET/CT, regardless the interpretation criteria used and it can be, therefore, used in early post-surgical phases or to confirm or rule out a PET/CT finding. Conclusions - After CTA, patients with suspected late VGEI should perform a [F-18]FDG PET/CT given its high sensitivity and NPV. However, given its lower specificity, positive results should be confirmed with Tc-99m-WBC scintigraphy. The use of a more detailed scoring system reduces the number of Tc-99m-WBC scans needed after [F-18]FDG PET/CT. Nevertheless, in suspected infections within 4 months from surgery, Tc-99m-WBC SPECT/CT should be performed as second exam, due to its high accuracy in differentiating sterile inflammation from infection

Retrieving magma composition from TIR spectra: implications for terrestrial planets investigations

Emissivity and reflectance spectra have been investigated on two series of silicate glasses, having compositions belonging to alkaline and subalkaline series, covering the most common terrestrial igneous rocks. Glasses were synthesized starting from natural end-members outcropping at Vulcano Island (Aeolian Islands, Italy) and on Snake River Plain (USA). Results show that the shift of the spectra, by taking Christiansen feature (CF) as a reference point, is correlated with SiO2 content, the SCFM factor and/or the degree of polymerization state via the NBO/T and temperature. The more evolved is the composition, the more polymerized the structure, the shorter the wavelength at which CF is observable. CF shift is also dependent on temperature. The shape of the spectra discriminates alkaline character, and it is related to the evolution of Qn structural units. Vulcano alkaline series show larger amount of Q4 and Q3 species even for mafic samples compared to the subalkaline Snake River Plain series. Our results provide new and robust insights for the geochemical characterization of volcanic rocks by remote sensing, with the outlook to infer origin of magmas both on Earth as well as on terrestrial planets or rocky bodies, from emissivity and reflectance spectra

Teacher confidence in professional training: The predictive roles of engagement and burnout

Teachers' work engagement positively impacts teachers' attitudes towards their job. Nevertheless, teachers may experience burnout during their career, which negatively impacts their professional learning opportunities. In this study we investigated the relationship between teachers' levels of burnout, work engagement, and their confidence in in-service training in a sample of Italian teachers. We expected that burnout mediated the relationship between work engagement and teachers' confidence in training. A total of 481 teachers completed self-report questionnaires about engagement and burnout, with an ad hoc Confidence in Training Index developed to assess their attitudes towards professional development courses. The mediation analysis confirmed that the teachers' levels of burnout mediated the relationship between their work engagement and their confidence in in-service training. Findings suggest that teacher confidence in policies about professional training should be evaluated by taking into account their level of engagement and burnout

Prognostic Relevance of Neutrophil to Lymphocyte Ratio (NLR) in Luminal Breast Cancer: A Retrospective Analysis in the Neoadjuvant Setting

The neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A- or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR: 6.97, 95% CI: 1.65-10.55, p = 0.002) and OS (HR: 7.79, 95% CI: 1.25-15.07, p = 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67 ≥ 14% were also associated with worse DFS (p = 0.016, p = 0.002, and p = 0.001, respectively). In a multivariate analysis, luminal B subtype, post-treatment Ki67 ≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67 ≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT

Interleukin-15 is required for immunosurveillance and immunoprevention of HER2/neu-driven mammary carcinogenesis

We previously demonstrated that HER2/neu-driven mammary carcinogenesis can be prevented by an interleukin-12 (IL-12)-adjuvanted allogeneic HER2/neu-expressing cell vaccine. Since IL-12 can induce the release of interleukin-15 (IL-15), in the present study we investigated the role played by IL-15 in HER2/neu driven mammary carcinogenesis and in its immunoprevention

Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state

Electrochemotherapy of skin metastases from malignant melanoma: a PRISMA-compliant systematic review

The main treatment of MM metastases are systemic therapies, surgery, limb perfusion, and intralesional talimogene laherparepvec. Electrochemotherapy (ECT) is potentially useful also due to the high response rates recorded in cancers of any histology. No randomized studies comparing ECT with other local therapies have been published on this topic. We analyzed the available evidence on efficacy and toxicity of ECT in this setting. PubMed, Scopus, and Cochrane databases were screened for paper about ECT on MM skin metastases. Data about tumor response, mainly in terms of overall response rate (ORR), toxicity (both for ECT alone and in combination with systemic treatments), local control (LC), and overall survival (OS) were collected. The methodological quality was assessed using a 20-item validated quality appraisal tool for case series. Overall, 18 studies were included in our analysis. In studies reporting “per patient” tumor response the pooled complete response (CR) was 35.7% (95%CI 26.0–46.0%), and the pooled ORR was 80.6% (95%CI 68.7–90.1%). Regarding “per lesion” response, the pooled CR was 53.5% (95%CI 42.1–64.7%) and the pooled ORR was 77.0% (95%CI 56.0–92.6%). One-year LC rate was 80%, and 1-year OS was 67–86.2%. Pain (24.2–92.0%) and erythema (16.6–42.0%) were the most frequent toxicities. Two studies reported 29.2% and 41.6% incidence of necrosis. ECT is effective in terms of tumor response and tolerated in patients with skin metastases from MM, albeit with a wide variability of reported results. Therefore, prospective trials in this setting are warranted

p130Cas is an essential transducer element in ErbB2 transformation

The ErbB2 oncogene is often overexpressed in breast tumors and associated with poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration, and proliferation in normal and pathological cells. The functional role of p130Cas in ErbB2-dependent breast tumorigenesis was assessed by its silencing in breast cancer cells derived from mouse mammary tumors overexpressing ErbB2 (N202-1A cells), and by its reexpression in ErbB2-transformed p130Cas-null mouse embryonic fibroblasts. We demonstrate that p130Cas is necessary for ErbB2-dependent foci formation, anchorage-independent growth, and in vivo growth of orthotopic N202-1A tumors. Moreover, intranipple injection of p130Cas-stabilized siRNAs in the mammary gland of Balbc-NeuT mice decreases the growth of spontaneous tumors. In ErbB2-transformed cells, p130Cas is a crucial component of a functional molecular complex consisting of ErbB2, c-Src, and Fak. In human mammary cells, MCF10A.B2, the concomitant activation of ErbB2, and p130Cas overexpression sustain and strengthen signaling, leading to Rac1 activation and MMP9 secretion, thus providing invasive properties. Consistently, p130Cas drives N202-1A cell in vivo lung metastases colonization. These results demonstrate that p130Cas is an essential transducer in ErbB2 transformation and highlight its potential use as a novel therapeutic target in ErbB2 positive human breast cancers.-Cabodi, S., Tinnirello, A., Bisaro, B., Tornillo, G., Camacho-Leal, M. P., Forni, G., Cojoca, R., Iezzi, M., Amici, A., Montani, M., Eva, A., Di Stefano, P., Muthuswamy, S. K., Tarone, G., Turco, E., Defilippi, P. p130Cas is an essential transducer element in ErbB2 transformation